Nephrotic syndrome (NS) is characterized by heavy proteinuria, hypoalbuminemia, and increased risk of progressive loss of kidney function. It causes serious morbidity and high mortality, accounting for 15% of prevalent end-stage renal disease at an annual cost of more than $3 billion in the US. There is no effective treatment for most cases of NS associated with genetic mutations. Our research has been focused on a monogenic form of NS caused by missense mutations of LAMB2, one of the most commonly mutated genes in NS. Laminin 2 encoded by LAMB2 is a component of laminin-521 ( 5 2 1), the major laminin trimer of the glomerular basement membrane (GBM). Using our established cell and knockout/transgenic mouse models, we have found that inhibited secretion of misfolded C321R-LAMB2 from podocytes to the GBM and the resulting podocyte endoplasmic reticulum (ER) stress lead to proteinuria. In addition, increased accumulation of the mutant in the GBM alleviates proteinuria. Therefore, restoring defective trafficking of the mutant laminin and rescuing misfolded 2 proteins to reach their functional destination are hopeful therapeutic strategies. The overall goal of this research is to investigate a novel strategy for therapeutic intervention in genetic forms of NS. To accomplish our research goal, we have generated a NS mouse model (Lamb2-/-; NEPH- C321R-LAMB2 mice) in which podocyte-targeted expression of the mutant form of rat LAMB2 (C321R-LAMB2) via the mouse nephrin promoter (NEPH) replaces the wild-type mouse LAMB2. Our preliminary data show that the misfolded mutant protein is much more susceptible to protein degradation, which is mediated by the ubiquitin-proteasome pathway. More excitingly, a combination of a chemical chaperone correcting protein misfolding and a proteasome inhibitor blocking protein degradation elicit a much more pronounced pro- secretion effect as compared to the chemical chaperone alone in vitro. Thus, the effect of combined treatment regulating both protein misfolding and degradation will be further investigated in our NS mouse model. The proposed study will assay the feasibility for therapeutic use of chemical chaperones in combination with proteasome inhibitors in a NS animal model. The results may have significant therapeutic implications for the treatment of familial or sporadic NS patients caused by aberrant ER proteostasis and podocyte ER dysfunction.